Large-Scale 3–5 Hz Oscillation Constrains the Expression of Neocortical Fast Ripples in a Mouse Model of Mesial Temporal Lobe Epilepsy

Abstract

Large-scale slow oscillations allow the integration of neuronal activity across brain regions during sensory or cognitive processing. However, evidence that this form of coding also holds for pathological networks, such as for distributed networks in epileptic disorders, does not yet exist. Here, we show in a mouse model of unilateral hippocampal epilepsy that epileptic fast ripples generated in the neocortex distant from the primary focus occur during transient trains of interictal epileptic discharges. During these epileptic paroxysms, local phase-locking of neuronal firing and a phase–amplitude coupling of the epileptic discharges over a slow oscillation at 3–5 Hz are detected. Furthermore, the buildup of the slow oscillation begins in the bihippocampal network that includes the focus, which synchronizes and drives the activity across the large-scale epileptic network into the frontal cortex. This study provides the first functional description of the emergence of neocortical fast ripples in hippocampal epilepsy and shows that cross-frequency coupling might be a fundamental mechanism underlying the spreading of epileptic activity.

The Role of EEG-fMRI in Studying Cognitive Network Alterations in Epilepsy

“…Epilepsy cannot be reduced solely to the dysfunction of the seizure onset zone (SOZ), as more widespread abnormalities can be seen, resulting in heterogeneous deficits across cognitive domains (1–6). This supports the view that epilepsy is a network disease associated with complex cognitive deficits (7–11). While these cognitive deficiencies are increasingly recognized as important co-morbidities of epileptic disorders, they are still insufficiently understood and investigated.…”

“…The use of combined EEG-fMRI in animal models, and in particular animal models of epilepsy, comes with two major benefits: first, it allows us to control for more parameters than in human research, thus providing more insights into the biological substrates of the BOLD signal, as illustrated by studies using optogenetic tools (65). Second, it gives access to the epileptic network (10, 11, 75), as it offers the opportunity to sample multiple brain regions related to the activity of the epileptic focus, with much higher spatial and temporal resolution in comparison to studies in humans (76).…”

“…Future studies could also address the relationship between IEDs and brain rhythms (11, 17), and how this disrupts normal cognitive processing, which are known to rely on specific brain oscillatory activity (19, 20, 112–114).…”

Neurostimulation and Therapeutic Advance: Iterative or Principled?

“…Due to their ubiquity throughout the brain they are capable of coordinating with global (proposed to occur through slower oscillations like theta and delta waves), and/or regional (thought to involve gamma waves) activities [12]. The effect of cross frequency coupling in epilepsy, for example, is known to underlie the distribution of epileptogenesis throughout the cortex [13]. Resonating in unison has the important effect of enabling information transfer and so of regulating communication between brain domains [14].…”

Rodent EEG: Expanding the Spectrum of Analysis

“…[36][37][38] Consistent with these findings, aberrant PAC in the hippocampus and neocortex in rodent models of mesial temporal lobe epilepsy (MTLE) has been linked to poor performance on memory tasks. 39,40 Thetagamma and theta HFO coupling have also been described in the parietal cortex of wild-type mice, with a strong dependence on sleep state. 41 Aberrant parietal PAC has been identified in the awake background of mouse models of absence epilepsy, even after seizures have been pharmacologically treated.…”